Abstract

2848

Head and neck cancer accounts for 4-6% of all human cancers. Squamous cell carcinoma of the head and neck (SCCHN) is a lethal cancer with one of the lowest five-year survival rates. Combination of the chemotherapeutic agent cisplatin and radiation therapy is commonly used as a treatment for this cancer. Our laboratory and others have shown that loss of expression of the tumor suppression gene p16 (also known as cyclin dependent kinase 4 inhibitor) correlates with a poor prognosis in head and neck cancer. Studies using immunohistochemical analysis of 40 head and neck tumors have shown that patients with nuclear p16 expression have better prognosis and longer survival as compared to those with cytoplasmic or no p16 expression. Analysis of several different SCCHN cell lines for cisplatin sensitivity showed CCL23, the cell line with nuclear p16 expression, to be most sensitive. This sensitivity was accompanied by an increased nuclear localization of the p16 protein after treatment with cisplatin. The other cell lines which did not express p16 were resistant to cisplatin. There was also a correlation between the nuclear expression of p16 and reduced phosphorylation of the Rb tumor suppressor gene in the various cell lines. Thus increased nuclear expression of p16 seems to result in enhanced sensitivity to cisplatin. In order to verify these results we have employed Si RNA to reduce the expression of p16 in CCL23 cells and are attempting to express p16 in non expressing cells using an RCR (replication competent retroviral) gene delivery vector. Introduction of the p16 Si RNA has shown a reduced nuclear expression of p16 protein in CCL23 cells. Like wise we have also seen enhanced nuclear p16 expression in RCR-p16 transfected cells. We hope that these model systems will be useful to demonstrate a direct correlation between nuclear p16 expression and sensitivity to cisplatin in head and neck cancer.